Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXQSJ1J)

• DOT Name: Sorting nexin-1 (SNX1)
• Gene Name: SNX1
• Related Disease:
  Advanced cancer
  Carcinoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Essential hypertension
  Gastric cancer
  High blood pressure
  Insulinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Salmonella infection
  Stomach cancer
  Non-small-cell lung cancer
• UniProt ID: SNX1_HUMAN
• PDB ID: 2I4K; 4FZS; 8A1G; 8ABQ; 8AFZ
• Pfam ID: PF00787 ; PF03700 ; PF09325
• Sequence:
  MASGGGGCSASERLPPPFPGLEPESEGAAGGSEPEAGDSDTEGEDIFTGAAVVSKHQSPK
  ITTSLLPINNGSKENGIHEEQDQEPQDLFADATVELSLDSTQNNQKKVLAKTLISLPPQE
  ATNSSKPQPTYEELEEEEQEDQFDLTVGITDPEKIGDGMNAYVAYKVTTQTSLPLFRSKQ
  FAVKRRFSDFLGLYEKLSEKHSQNGFIVPPPPEKSLIGMTKVKVGKEDSSSAEFLEKRRA
  ALERYLQRIVNHPTMLQDPDVREFLEKEELPRAVGTQTLSGAGLLKMFNKATDAVSKMTI
  KMNESDIWFEEKLQEVECEEQRLRKLHAVVETLVNHRKELALNTAQFAKSLAMLGSSEDN
  TALSRALSQLAEVEEKIEQLHQEQANNDFFLLAELLSDYIRLLAIVRAAFDQRMKTWQRW
  QDAQATLQKKREAEARLLWANKPDKLQQAKDEILEWESRVTQYERDFERISTVVRKEVIR
  FEKEKSKDFKNHVIKYLETLLYSQQQLAKYWEAFLPEAKAIS
• Function: Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) (Probable). Can sense membrane curvature and has in vitro vesicle-to-membrane remodeling activity. Involved in retrograde endosome-to-TGN transport of lysosomal enzyme receptors (IGF2R, M6PR and SORT1) and Shiginella dysenteria toxin stxB. Plays a role in targeting ligand-activated EGFR to the lysosomes for degradation after endocytosis from the cell surface and release from the Golgi. Involvement in retromer-independent endocytic trafficking of P2RY1 and lysosomal degradation of protease-activated receptor-1/F2R. Promotes KALRN- and RHOG-dependent but retromer-independent membrane remodeling such as lamellipodium formation; the function is dependent on GEF activity of KALRN. Required for endocytosis of DRD5 upon agonist stimulation but not for basal receptor trafficking.
• KEGG Pathway: Endocytosis (hsa04144)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[2]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Essential hypertension	DIS7WI98	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[1]
High blood pressure	DISY2OHH	Strong	Biomarker	[4]
Insulinoma	DISIU1JS	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Posttranslational Modification	[6]
Lung carcinoma	DISTR26C	Strong	Posttranslational Modification	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Salmonella infection	DISTJ434	Strong	Biomarker	[7]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[8]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sorting nexin-1 (SNX1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sorting nexin-1 (SNX1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sorting nexin-1 (SNX1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sorting nexin-1 (SNX1).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Sorting nexin-1 (SNX1).	[14]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Sorting nexin-1 (SNX1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sorting nexin-1 (SNX1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sorting nexin-1 (SNX1).	[19]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Sorting nexin-1 (SNX1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Sorting nexin-1 (SNX1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sorting nexin-1 (SNX1).	[17]

References

• [1] Sorting nexin-1 is a candidate tumor suppressor and potential prognostic marker in gastric cancer.PeerJ. 2018 May 29;6:e4829. doi: 10.7717/peerj.4829. eCollection 2018.
• [2] Sorting nexin 1 down-regulation promotes colon tumorigenesis.Clin Cancer Res. 2006 Dec 1;12(23):6952-9. doi: 10.1158/1078-0432.CCR-06-0317.
• [3] Down-regulation of SNX1 predicts poor prognosis and contributes to drug resistance in colorectal cancer.Tumour Biol. 2016 May;37(5):6619-25. doi: 10.1007/s13277-015-3814-3. Epub 2015 Dec 7.
• [4] Sorting nexin 1 loss results in D5 dopamine receptor dysfunction in human renal proximal tubule cells and hypertension in mice.J Biol Chem. 2013 Jan 4;288(1):152-63. doi: 10.1074/jbc.M112.428458. Epub 2012 Nov 14.
• [5] A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic -Cells.Diabetes. 2018 Mar;67(3):385-399. doi: 10.2337/db17-0639. Epub 2017 Dec 28.
• [6] Silencing of SNX1 by siRNA stimulates the ligand-induced endocytosis of EGFR and increases EGFR phosphorylation in gefitinib-resistant human lung cancer cell lines.Int J Oncol. 2012 Oct;41(4):1520-30. doi: 10.3892/ijo.2012.1578. Epub 2012 Jul 31.
• [7] Sorting nexin-1 defines an early phase of Salmonella-containing vacuole-remodeling during Salmonella infection.J Cell Sci. 2008 Jun 15;121(Pt 12):2027-36. doi: 10.1242/jcs.018432. Epub 2008 May 27.
• [8] Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non-Small Cell Lung Cancer Cells.Mol Cancer Res. 2019 May;17(5):1207-1219. doi: 10.1158/1541-7786.MCR-18-0731. Epub 2019 Jan 15.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.